Considerable experimental and epidemiological evidence link atherosclerosis to inflammation. Atherosclerosis in humans requires decades to develop, and does so on a background of recurrent infectious and inflammatory stimuli. As T cells are central to all acquired immunity, this proposal focuses on the hypothesis that CD4 T cells modulate atherosclerosis by their control of inflammatory cells and biochemical mediators. We propose to use a well-characterized murine model of CD4 T cell-induced cardiac-specific injury to provide the inflammatory stimulus upon which to study how T cells modulate atherogenesis. This project represents a new direction of investigation with this model system, attempting to identify important cellular and biochemical links between inflammation and atherosclerosis. We present preliminary data demonstrating two important findings. First, we show that CD4 T cell-mediated inflammatory responses accelerates the onset of atherosclerosis in the fat-fed mouse model. Second, we show that a CD4 T cell mediated inflammatory response augments the progression of atherosclerosis by increasing the surface area of aortic root plaque in the fat fed mice. Aim 1 characterizes and quantitates the effect of a CD4 T cell-mediated immune response on the kinetics and extent of plaque formation, and defines the Th subset dominance during the induction of inflammation. Our preliminary data supports the feasibility of this aim. Aim 2 examines the effect of Th cell subset dominance on macrophage function in mice with active cardiac inflammation and atherosclerosis. We will analyze antigen processing and presentation, costimulation, matrix metalloproteinase release, and oxidative modifications of lipoproteins. Aim 3 studies the effect of directly skewing Th differentiation on the pathogenesis of atherosclerosis in IL-4 deficient mice, which are unable to make Th2 calls. Overall the goal of these studies is to understand how T cell mediated inflammation and immunity modulate atherosclerosis.